Facile synthesis of α-alkoxymethyltriphenylphosphonium iodides: new application of PPh3/I2

An efficient one pot method for the synthesis of α-alkoxymethylphosphonium iodides is developed by using PPh3/I2 combination at room temperature. Reaction conditions are found general to synthesize wide range of structurally variant alkoxymethylphosphonium iodides in high yield (70–91%). These new functionalized phosphonium salts are further used in stereoselective synthesis of vinyl ethers as well as in carbon homologation of aldehydes. Electronic supplementary material The online version of this article (10.1186/s13065-018-0421-6) contains supplementary material, which is available to authorized users.


Results and discussion
Current study was initiated from the model reaction of bis-butoxy methane (1a) with PPh 3 /I 2 combination under different conditions (Table 1). Our preliminary attempt was encouraging, where 27% desired conversion (2a) was observed on refluxing equal molar amounts of acetal (1a) and PPh 3 /I 2 in toluene for an hour (Table 1, entry 1). To improve the yield, reaction time was increased up to 3 h but only 33% required conversion was observed (Table 1, entry 2). Low yield might be associated with the sublimation of iodine at high temperature therefore, it was considered to decrease the reaction temperature. To our delight, yield was increased to 55% when the same experiment was performed at room temperature (Table 1,  entry 3). Increasing the amount of PPh 3 to 2 equivalent and reaction time up to 5 h further improved the yield (80%) ( Table 1, entry 4). However, further attempts with increase in reaction time and replacing toluene with acetonitrile or solvent free conditions, were not effectual (Table 1, entry 5-8).
To explore the substrate scope of this reaction, optimized conditions were employed to structurally different bis-alkoxy methanes (1a-j, see Additional file 1) [33]. The method was found equally efficient to obtain broad range of alkoxymethylphosphonium iodides (2a-j, Table 2) based on primary, secondary, tertiary and benzylic alkoxy groups. Acetals having simple methoxy, ethoxy, benzoxy and phenylethoxy groups provided desired O,P-acetals 2b-e in 75-87%. Similarly, when acetal of (S)-2-butanol was reacted with PPh 3 /I 2 , corresponding salt 2f was obtained in 90% yield with retention in configuration, which was ultimately confirmed by X-ray diffraction analysis (Fig. 1).
Optimized reaction conditions were further extended to cyclic chiral alkoxy groups including fenchyl, menthyl and borneyl, where respective chiral phosphonium salts 2g-i were obtained in good yields (Table 2).
Here, (+)-menthoxymethyltriphenylphosphonium iodide 2h is worth mentioning as its chloride analogue was prepared by tedious methodology with long reaction time [12]. Interestingly, the reaction was also successful with acetal of t-butanol where corresponding salt 2j was produced in 77% yield ( Table 2).
In terms of mechanism, we envision that initially I 2 and PPh 3 generate phosphonium intermediate (i), which reacts with bis-alkoxymethane 1 to provide oxonium intermediate (ii) (Scheme 2). Another equivalent of PPh 3 attack on oxonium intermediate (ii) to transform it into the target O,P-acetal 2 (Scheme 2).
Further, cost effective n-butoxymethylphosphonium iodide 2a was employed for carbon homologation, where both aliphatic and aromatic aldehydes were successfully converted to higher analogous 4 in good yield (Table 4). Results show that these directly prepared and environmentally benign salts are good alternative to their chloride analogues.
Detailed study and further investigation on the application of these structurally unique α-alkoxymethylphosphonium salts in stereoselective synthesis of enol ethers carrying chiral auxillaries as well as in other related fields are currently underway in our laboratory.

Conclusion
In conclusion, a facile general method for the synthesis of α-alkoxymethyl triphenylphosphonium iodides is developed under very mild conditions. This protocol demonstrates PPh 3 /I 2 mediated green route to functionalized phosphonium salts. Major advantage of this methodology is to avoid toxic reagent and intermediate. These easily prepared salts were successfully employed for stereoselective synthesis of enol ethers as well as for carbon homologation in aldehydes. The new methodology will be useful for organic synthetic chemists as well as others working in associated fields.

Experimental
All experiments were carried out under inert atmosphere using standard Schlenk technique with oven dried glassware and magnetic stirring. All solvents were freshly dried and distilled before use. All chemicals were purchased from Sigma Aldrich, Alfa Aesar and Merck. IR spectra were measured on a Perkin-Elmer Paragon 1000 (thin film) or on a Perkin-Elmer BXII spectrometer (neat). Bruker Avance NMR spectrometer of 300, 400 and 500 MHz were used for NMR spectral studies. Optical rotation was measured on Polarimeter P-2000. Crystal structure was confirmed by single crystal X-ray diffractometer Bruker Enrauf-Nonius Apex smart and Siemens P4. Mass spectra were measured on GC-MS 5977A, MAT312-EI, JEOL-600H-2, and JEOL MS-600H-1. Reactions were monitored by TLC plates from Merck (silica gel 60 F 254 , aluminum oxide 60 F 254 ). TLCs were visualized by UV fluorescence and phosphomolybdic acid spraying reagent.

General procedure for synthesis of α-alkoxymethyltriphen ylphosphonium iodides (2a-j)
In a seal tube triphenylphosphine (20 mmol) and iodine (1.1 equiv) were taken in toluene (4 mL) and mixture was allowed to stir for 5 min. Solution of bis-alkoxymethane (1, 10 mmol in 1 mL toluene) was added to the reaction mixture and allowed to stir for 5 h at room temperature (28 °C). After completion of reaction, solvent was removed under reduced pressure and residue was washed with hexane to obtain required salt.

General method for synthesis of vinyl ethers 3a-e
In a two neck round bottom flask n-BuLi (1.5 eq) was added to stirred solution of phosphonium iodide 2 (1 eq) in THF at − 78 °C and mixture was allowed to stir under argon. After 20 min solution of aldehyde (1 eq) in THF was added drop wise at the same temperature and reaction mixture was allowed to stir for further 4 h allowing the temperature to come to room temperature slowly. Reaction was monitored on TLC, after completion reaction was quenched with methanol and solvent was evaporated under reduced pressure. Products were purified on silica gel column by combinations of ethyl acetate and pet ether as eluent.

General method for carbon homologation in aldehydes
In a two neck round bottom flask containing phosphonim iodide 2a (1 eq) in dry THF (5 mL), n-BuLi (1.5 eq) was added dropwise at − 78 °C and mixture was allowed to stir for 30 min. Solution of aldehyde (1 eq) in THF was added dropwise to the phosphorene reaction mixture and further allowed to stir for 5 h. After acidic hydrolysis, crude product was extracted with EtOAc (10 mL × 2). Combined extract was dried over Na 2 SO 4 , concentrated and purified on preparative TLC (silica gel) to obtain higher analogue of aldehydes (see Additional file 1).

General procedure for asymmetric reduction reaction
In a two-neck round bottom flask, acetophenone (1.5 mmol), NaBH 4 (2.25 mmol) along with iodide salt 2g (10 mol%) was taken in methanol (5 mL). Reaction mixture was stirred for 2 h at room temperature. The reaction progress was monitored by TLC and after completion; the mixture was quenched with water and extracted EtOAc (2 × 3 mL). Combined organic layer was dried over MgSO 4 and the solvent was evaporated under reduced pressure to afford the corresponding (R)-1-phenylethanol (92% yield, 4% ee). Enantiomeric excess (ee) was calculated on HPLC using chiral cellulose OD-H column, hexane/i-PrOH, 95:5, flow rate 1 mL/min (see Additional file 1).